Stress Related Shift Toward Inflammaging in Cosmonauts After Long-Duration Space Flight.

Judith-Irina Buchheim,Detlef Thieme,Katharina Biere,Sergey Ponomarev,Manfred Thiel,Manfred Thiel,Manfred Thiel,Galina Vassilieva,Marina Rykova,Matthias Feuerecker,Dominique Moser,Igor Nichiporuk,Ines Kaufmann,Gustav Schelling,Alexander Choukèr,Marion Hörl,Sandra Matzel

doi:10.3389/fphys.2019.00085

Abstract

Space flight exerts a specific conglomerate of stressors on humans that can modulate the immune system. The mechanism remains to be elucidated and the consequences for cosmonauts in the long term are unclear. Most of the current research stems from short-term spaceflights as well as pre- and post-flight analyses due to operational limitations. Immune function of 12 cosmonauts participating in a long-duration (>140 days) spaceflight mission was monitored pre-, post-, and on two time-points in-flight. While the classical markers for stress such as cortisol in saliva where not significantly altered, blood concentrations of the endocannabinoid system (ECS) were found to be highly increased in-flight indicating a biological stress response. Moreover, subjects showed a significant rise in white blood cell counts. Neutrophils, monocytes and B cells increased by 50% whereas NK cells dropped by nearly 60% shortly after landing. Analysis of blood smears showed that lymphocyte percentages, though unchanged pre- and post-flight were elevated in-flight. Functional tests on the ground revealed stable cellular glutathione levels, unaltered baseline and stimulated ROS release in neutrophils but an increased shedding of L-selectin post-flight. In vitro stimulation of whole blood samples with fungal antigen showed a highly amplified TNF and IL-1β response. Furthermore, a significant reduction in CD4+CD25+CD27low regulatory T cells was observed post-flight but returned to normal levels after one month. Concomitantly, high in-flight levels of regulatory cytokines TGF-β, IL-10 and IL-1ra dropped rapidly after return to Earth. Finally, we observed a shift in the CD8+ T cell repertoire toward CD8+ memory cells that lasted even one month after return to Earth.Conclusion: Long-duration spaceflight triggered a sustained stress dependent release of endocannabinoids combined with an aberrant immune activation mimicking features of people at risk for inflammation related diseases. These effects persisted in part 30 days after return to Earth. The currently available repertoire of in-flight testing as well as the post-flight observation periods need to be expanded to tackle the underlying mechanism for and consequences of these immune changes in order to develop corresponding mitigation strategies based on a personalized approach for future interplanetary space explorations.

Highlights

Long-duration missions to the Moon and Mars are the ultimate goals for human space exploration
Classical stress hormones like cortisol driven by the hypothalamic-pituitary-adrenal (HPA) axis or the catecholamines norepinephrine and epinephrine have been shown to interfere with immune responses (Sorrells and Sapolsky, 2007)
The protocol was evaluated by the Russian ethical board (Biomedicine Ethics Committee) at the Institute of Biomedical Problems (IBMP), Moscow, and was awarded the protocol number MBI-29 under the Title “IMMUNO.” The protocol was approved by the European Space Agency (ESA) medical board and the Russian Space Agency (Roscosmos)

Summary

Introduction

Long-duration missions to the Moon and Mars are the ultimate goals for human space exploration. A constant exposure to a stressful environment together with a constant exposure to antigens and an ongoing inflammatory response can result in a pathogenic phenotype showing features of premature immune aging, with increased cytokine responses and the accumulation of memory and effector T cells (Fagiolo et al, 1992; Franceschi et al, 2000; De Martinis et al, 2005) This so called “inflammaging” is a low-grade, pro-inflammatory state that renders its host at risk for latent viral infections, allergic or autoimmune disease as seen in elderly patients (Ravaglia et al, 2003; Pawelec and Gouttefangeas, 2006; Bauer and Fuente Mde, 2016; Sanada et al, 2018). There are indications that space travel might promote such an agerelated inflammatory phenotype prematurely as crew members spend a considerably long time in such an environment and viral shedding and skin exanthema occur frequently in flight (Mehta et al, 2014; Crucian et al, 2016)

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